Project Abstract This new grant application is in response to the ?Martin Delaney Collaboratories for HIV Cure Research (UM1)? RFA. We call our application ?BELIEVE?, short for ?Bench to Bed Enhanced Lymphocyte Infusions to Engineer Viral Eradication?. One individual, known as the ?Berlin patient?, is considered to be cured of HIV, with no evidence for active replication competent virus in the absence of antiretroviral (ARV) therapy. The ?Mississippi? baby initially appeared to be another cure, but virus re-emerged a couple of years after ARV cessation. ARV therapy prolongs life, but a life expectancy gap shows patients on viral suppressive therapies live a shorter life, and have more co-morbidities. To help end the epidemic, an HIV cure is needed. Current ?shock and kill? strategies are limited in harnessing the power of immunity in seeking and removing latent cells. Augmentation of immunity could be performed through vaccination, although therapeutic vaccination in HIV infection has had limited efficacy to date. In addition, immune effectors in HIV infected persons are not fully recovered with ARV treatment. There are at least three mechanisms which lead to the inability of the immune system to remove virus completely: (1) a weakened and exhausted cytotoxic T- lymphocyte (CTL) response from which epitope escape has occurred, (2) over activated but under performing Natural Killer cells, and (3) inability of effector cells to reach the right sites where latent virus reside. Our proposal has objectives, broadly defined, that are aimed at understanding how to enhance the killing ability of HIV specific cytotoxic T lymphocytes, to augment NK cell functions, and to harness T-cell, NK cell and antibody mediated effectors in the context of adult and pediatric HIV infections. First, we will immediately initiate a pilot clinical study with our most promising combination of T-cell infusion and latency-reversing agents. We will compare this combination to enhanced natural and engineered T-cells to eradicate HIV reservoirs (in vitro, in mice, in non-human primates, and in additional human clinical studies), in association with novel HIV Nef small molecule inhibitors. Second, we will develop and test enhanced Natural Killer cells with or without broadly neutralizing antibodies (in mice, in non human primates, and in humans). Third, we will target sites of viral latency which CTL cannot reach, by targeting CTL to home to reservoir sites. We have gathered a group of accomplished investigators, with strong collaborative histories, along with community advisors. Around 40% of the scientific leadership positions are women, and there are representatives of early stage and minority investigators, and two corporate partners, all driven by the belief that a cure will depend on enhancing anti-HIV immunity in association with latency reversal.